The Washington University Center for Multiple Myeloma Nanotherapy (WU CMMN) will address overarching questions in bone malignancies, with a focus on multiple myeloma (MM). MM is a hematopoietic malignancy caused by terminally differentiated malignant plasma B-cells. Myeloma cells simultaneously activate the bone resorbing osteoclast cells in the bone marrow and inhibit bone forming osteoblast cells, culminating in a vicious cycle of tumor growth and bone destruction. A grim result of this interplay is that 80% of MM patients present bone lesions including pathologic fracture at diagnosis. Despite tremendous improvements in MM patient management, more than 24,000 new cases and 11,000 deaths occurred in 2014 alone. Additionally, the side effects of chemotherapeutics can result in increased risk of systemic toxicity and hospitalization costs. An impaired bone marrow reserve imposes additional constraints on how best to deliver therapy without producing worsening cytopenias and further increasing the risk for complications. About 10% of patients have primary refractory disease and fail to respond to induction treatments. Thus, although newer molecular therapeutics may extend patient survival, nearly all patients will eventually relapse and die from MM. The long-term goal of our CMMN is to provide curative outcomes by developing novel nanotherapeutics that utilizes unique drug delivery mechanism and multidimensional treatment paradigms to accomplish our goal. Anchored by 3 projects and two cores, we aim to (1) develop integrated curative approach for the treatment of MM with minimal off target toxicity; (2) identify nanotherapeutics for clinical translation; (3) provide a platform to educate, train, and mentor young investigators and students on techniques and methods of cancer nanomedicine; (4) create environment for productive outreach programs that brings researchers and patients together through workshops and seminars; and (5) collaborate with other CCNEs and investigators in the region to share information and resources with a goal to accelerating clinical translation of nanomedicine to human patients. Beyond MM, successful completion of the proposed research will advance the treatment of hematological diseases in general and usher new therapies for tackling the challenges in treating bone marrow metastasis.